The neutral proteinase collagenase is a major mediator of the joint destruction seen in rheumatoid arthritis, and when cultured in vitro, rheumatoid synovial cells "spontaneously" secrete large quantities of this enzyme into the medium. Treatment of cells with corticosteroids or with retinoids, at physiologic concentrations, inhibits production of the enzyme. Mechanisms controlling both the induction and inhibition of collagenase synthesis, however, are not known. Cultures of rabbit synovial fibroblasts are an excellent model for studies on the control of collagenase gene expression. Untreated cells secrete negligible amounts of collagenase, but treatment of cells with a variety of agents (phorbol myristate acetate, crystals of monosodium urate monohydrate) results after a 24-hour lag, in a several-hundred-fold increase in enzyme production. This is linked to an increase in levels of translatable messenger RNA for collagenase. Similarly, the decrease in collagenase synthesis occurs gradually, over a period of several days. By using recombinant DNA technology, we can begin to study molecular events involved in collagenase production. We plan to continue our efforts to isolate a cDNA clone for rabbit synovial fibroblast collagenase. We will use our clone as a probe to measure levels of mRNA in cells at intervals after addition of stimuli or inhibitors of collagenase synthesis, to isolate the genomic clone for collagenase and to determine whether induction and inhibition are under transcriptional control. These studies support our long term goal of understanding mechanisms controlling collagenase production in both normal and diseased states.